Exercise prehabilitation for people with myeloma undergoing autologous stem cell transplantation: results from PERCEPT pilot randomised controlled trial

BACKGROUND: Autologous stem cell transplant (ASCT) is first line treatment for newly diagnosed patients with myeloma but often results in functional deficits and reduced quality of life (QOL). Physically active myeloma patients have better QOL, less fatigue and reduced morbidity. This trial aimed to investigate the feasibility of a physiotherapist-led exercise intervention delivered across the continuum of the myeloma ASCT pathway at a UK centre. Initially designed and delivered as a face-to-face trial, the study protocol was adapted to virtual delivery in response to the COVID-19 pandemic. MATERIAL AND METHODS: A pilot randomised controlled trial of a partly supervised exercise intervention with incorporated behaviour change techniques delivered before, during and for 3 months following ASCT compared to usual care. Face-to-face delivery of the pre-ASCT supervised intervention was adapted to virtually-supervised group classes via video conferencing. Primary outcomes related to feasibility; recruitment rate, attrition and adherence. Secondary outcomes included patient reported measures of QOL (EORTC C30, FACT-BMT, EQ5D), and fatigue (FACIT-F), measures of functional capacity (six-minute walk test (6MWT), timed sit-to-stand (TSTS), hand grip strength, self-reported and objective physical activity (PA). RESULTS: Over 11 months 50 participants were enrolled and randomised. Overall, uptake to the study was 46%. The attrition rate was 34%, mainly related to failure to undergo ASCT. Loss of follow-up for other reasons was low. Secondary outcomes demonstrate potential for the benefit of exercise prior to, during and after ASCT with improvements in QOL, fatigue, functional capacity and PA evident on admission for ASCT and 3 months post-ASCT. DISCUSSION: Results indicate acceptability and feasibility of delivering exercise prehabilitation, in person and virtually within the ASCT pathway in myeloma. The effects of prehabilitation and rehabilitation provision as a component of the ASCT pathway warrants further investigation

"What I wanted to do was build myself back up and prepare": qualitative findings from the PERCEPT trial of prehabilitation during autologous stem cell transplantation in myeloma

BACKGROUND: The addition of qualitative methodology to randomised controlled trials evaluating complex interventions allows better understanding of contextualised factors and their potential influence on trial delivery and outcomes, as well as opportunities for feedback on trial participation to improve future trial protocols. This study explored the experiences of participation in cancer rehabilitation research during active cancer treatment. Participants were people living with haematological cancer myeloma, undergoing autologous stem cell transplantation (ASCT) recruited to the PERCEPT myeloma pilot trial. METHODS: A qualitative semi-structured interview study, embedded within a pilot randomised controlled trial of a physiotherapist-led exercise intervention delivered before, during and after ASCT among people living with myeloma. Transcripts were analysed using reflexive thematic analysis. RESULTS: Interviews from 16 trial participants (n = 8 intervention group; n = 8 control group; mean age 61 years, 56% male) were analysed. Four main themes were identified: (1) "It's not just beneficial for me, it's for people after me as well"; (2) Disparities in experience of recovery - expectations, feeling prepared and support; (3) "What I wanted to do was build myself back up and prepare"; (4) Active ingredients - participants' experience of the trial intervention. Participants reported both altruistic and perceived personal gain as motivators for enrolling in the trial. Disappointment caused by allocation to control arm may have led to participants seeking exercise elsewhere, indicating possible contamination of control condition. Disparities in experience of recovery from transplant were evident with intervention participants reporting greater trajectory of recovery. CONCLUSIONS: The findings from this embedded qualitative study highlight numerous considerations required when designing pilot and efficacy trials of complex interventions. The addition of qualitative investigation offers greater understanding of motivations for participation, intervention mechanisms at play as well as effects of participation that may impact interpretation of quantitative outcomes. TRIAL REGISTRATION: Qualitative findings from a prospectively registered pilot trial (ISRCTN15875290), registered 13/02/2019

Adaptation of the PERCEPT myeloma prehabilitation trial to virtual delivery: changes in response to the COVID-19 pandemic

Introduction and objective Research activity was impacted by the novel COVID-19 pandemic, the PERCEPT myeloma trial was no exception. This pilot randomised trial delivered a face-to-face exercise intervention prior to and during autologous stem cell transplantation (ASCT) in myeloma patients, as a consequence of COVID-19 it required significant adaptions to continue. This brief communication describes how the previously published study protocol was adapted for virtual delivery. In addition, we highlight the challenge of continuing the study which was embedded within a clinical pathway also impacted by the pandemic. Summary The original trial protocol was amended and continued to recruit and deliver an exercise prehabilitation intervention virtually. Continued delivery of the intervention was deemed important to participants already enrolled within the trial and the adapted virtual version of the trial was acceptable to the research ethics committee as well as participants. Development of effective, remotely delivered rehabilitation and physical activity programmes are likely to benefit people living with myeloma. The COVID-19 pandemic provided an opportunity to explore the feasibility of a virtual programme for ASCT recipients, however, continued changes to the clinical pathway within which the study was embedded posed the greatest challenge and ultimately led to early termination of recruitment. Trial registration number ISRCTN15875290; pre-result

Effects of nano-SiC addition on the superconducting properties of magnesium diboride

In this study, we report the results on phase formation, microstructures, and superconducting properties of a series of MgB2 samples with different level of SiC additions. The polycrystalline samples were prepared via solid state reaction by mixing magnesium, boron and silicone carbide powders according to the ratio of Mg:B:SiC = 1:2:x. XRD spectra showed that MgB2 is the primary phase while Mg2Si, MgO and MgB4, together with some unreacted SiC are the secondary phases as the addition increases. The presence of Mg2Si became more significant as the addition level increased. SEM images showed smaller grains as the addition level increases indicating more grain boundaries were formed. The Tc was as low as 30.5K for x=15wt%. The field dependence of Jc showed that x=1wt% sample gave the best performance at both 5K and 20K

Reaction method control of impurity scattering in C-doped MgB2: proving the role of defects besides C substitution level

In this study, Si and C were incorporated into polycrystalline MgB 2 via in situ reaction of Mg and B with either SiC or with separate Si and C (Si+C). The electrical transport and magnetic properties of the two series of samples were compared. The corrected resistivity at 40 K, ρA(40 K), is higher for the samples reacted with SiC regardless of the carbon (C) substitution level, indicating larger intragrain scattering because of the simultaneous reaction between Mg and SiC and carbon substitution during the formation of MgB2. In addition, because of the cleaner reaction route for the samples reacted with SiC, the calculated active area that carries current, AF, is twice that of the (Si+C) samples. On the other hand, the upper critical field, Hc2, was similar for both sets of samples despite their different C substitution levels, which proves the importance of defect scattering in addition to C substitution level. Hence, the form of the precursor reactants is critical for tuning the form of Hc2(T)

Deep learning enables spatial mapping of the mosaic microenvironment of myeloma bone marrow trephine biopsies

Bone marrow trephine biopsy is crucial for the diagnosis of multiple myeloma. However, the complexity of bone marrow cellular, morphological, and spatial architecture preserved in trephine samples hinders comprehensive evaluation. To dissect the diverse cellular communities and mosaic tissue habitats, we developed a superpixel-inspired deep learning method (MoSaicNet) that adapts to complex tissue architectures and a cell imbalance aware deep learning pipeline (AwareNet) to enable accurate detection and classification of rare cell types in multiplex immunohistochemistry images. MoSaicNet and AwareNet achieved an area under the curve of >0.98 for tissue and cellular classification on separate test datasets. Application of MoSaicNet and AwareNet enabled investigation of bone heterogeneity and thickness as well as spatial histology analysis of bone marrow trephine samples from monoclonal gammopathies of undetermined significance (MGUS) and from paired newly diagnosed and post-treatment multiple myeloma. The most significant difference between MGUS and newly diagnosed multiple myeloma (NDMM) samples was not related to cell density but to spatial heterogeneity, with reduced spatial proximity of BLIMP1+ tumor cells to CD8+ cells in MGUS compared with NDMM samples. Following treatment of multiple myeloma patients, there was a reduction in the density of BLIMP1+ tumor cells, effector CD8+ T cells, and T regulatory cells, indicative of an altered immune microenvironment. Finally, bone heterogeneity decreased following treatment of MM patients. In summary, deep-learning based spatial mapping of bone marrow trephine biopsies can provide insights into the cellular topography of the myeloma marrow microenvironment and complement aspirate-based techniques

MGP Panel is a comprehensive targeted genomics panel for molecular profiling of multiple myeloma patients

PURPOSE: We designed a comprehensive multiple myeloma (MM) targeted sequencing panel to identify common genomic abnormalities in a single assay and validated it against known standards. EXPERIMENTAL DESIGN: The panel comprised 228 genes/exons for mutations, 6 regions for translocations, and 56 regions for copy number abnormalities (CNAs). Toward panel validation, targeted sequencing was conducted on 233 patient samples and further validated using clinical fluorescence in situ hybridization (FISH) (translocations), multiplex ligation probe analysis (MLPA) (CNAs), whole genome sequencing (WGS) (CNAs, mutations, translocations) or droplet digital PCR (ddPCR) of known standards (mutations). RESULTS: Canonical IgH translocations were detected in 43.2% of patients by sequencing, and aligned with FISH except for one patient. CNAs determined by sequencing and MLPA for 22 regions were comparable in 103 samples and concordance between platforms was R2=0.969. VAFs for 74 mutations were compared between sequencing and ddPCR with concordance of R2=0.9849. CONCLUSIONS: In summary, we have developed a targeted sequencing panel that is as robust or superior to FISH and WGS. This molecular panel is cost effective, comprehensive, clinically actionable and can be routinely deployed to assist risk stratification at diagnosis or post-treatment to guide sequencing of therapies

Insights on multiple myeloma treatment strategies

The introduction of new agents and management strategies over the past decade has resulted in a major step change in treatment outcomes with deepening responses and increased survival for patients with multiple myeloma. In daily clinical practice, healthcare professionals are now faced with challenges including, optimal treatment sequencing and changing treatment goals. In light of this, a group of experts met to discuss diagnostic and treatment guidelines, examine current clinical practice, and consider how new clinical trial data may be integrated into the management of multiple myeloma in the future

Evaluation of the Taguchi methods for the simultaneous assessment of the effects of multiple variables in the tumour microenvironment

BACKGROUND: The control of proliferation, differentiation and survival of normal and malignant cells in the tumour microenvironment is under the control of a wide range of different factors, including cell:cell interactions, cytokines, growth factors and hormonal influences. However, the ways in which these factors interact are poorly understood. In order to compare the effects of multiple variables, experimental design becomes complex and difficult to manage. We have therefore evaluated the use of a novel approach to multifactorial experimental design, the Taguchi methods, to approach this problem. METHOD: The Taguchi methods are widely used by quality engineering scientists to compare the effects of multiple variables, together with their interactions, with a simple and manageable experimental design. In order to evaluate these methods, we have used a simple and robust system to compare a traditional experimental design with the Taguchi Methods. The effect of G-CSF, GM-CSF, IL3 and M-CSF on daunorubicin mediated cytotoxicity in K562 cells was measured using the MTT assay. RESULTS: Both methods demonstrated that the same combination of growth factors at the same concentrations minimised daunorubicin cytotoxicity in this assay. CONCLUSIONS: These findings demonstrate that Taguchi methods may be a valuable tool for the investigation of the interactions of multiple variables in the tumour microenvironment